Learning objectives

After reading this article you should be able to:

C outline the pathophysiology of secondary brain injury

C list mechanisms for physiological cerebroprotection

C list drugs used and their actions for pharmacological

cerebroprotection.

NEUROSURGICAL ANAESTHESIA

Clinical neuroprotection andsecondary neuronal injurymechanismsKatharine Hunt

Surbhi Virmani

Abstract

Multiple disease processes can ultimately lead to cerebral injury, a common

cause of both severe morbidity and mortality in patients of all age groups.

Cerebral injury is seen in a variety of both medical and surgical conditions,

including stroke, subarachnoid haemorrhage, central nervous system infec-

tion, epilepsy, post cardiac arrest and, of course, traumatic brain injury.

Although the primary damage to brain tissue may be irreversible,

aggressive early physiological, pharmacological and surgical interven-

tions may limit the ensuing secondary brain injury caused by ongoing

ischaemia, and reduce the risk of severe disability or death.

Keywords Cerebral protection; decompressive craniectomy; secondary

brain injury; stroke; traumatic brain injury

Royal College of Anaesthetists CPD matrix: 1A01, 1A02, 2F01

Secondary brain injury

Causes of secondary brain damage

Extracranial causesC Hypoxia

C Hypotension

C Metabolic

� Hyponatremia

The cascade of events that ultimately results in cerebral cell

death begins at the instant of primary brain injury. Following this

there are both local and systemic insults that may act alone, or

together to cause secondary brain injury (Box 1).

The most common factors leading to secondary brain injury

are hypoxia and hypoperfusion, which result in cellular

ischaemia, oedema formation, brain swelling, and disruption of

the bloodebrain barrier, thereby leading to an increase in

intracranial pressure that further reduces cerebral perfusion

setting up a vicious cycle of ischaemic insult.

� Hyperthermia

� Hypoglycemia/hyperglycaemia

Pathophysiology

Intracranial causes

C Haemorrhage

� Extradural

� Subdural

� Intracerebral

� Intraventricular

� Subarachnoid

C Swelling

� Venous congestion/hyperaemia

� Oedema

C Vasogenic

Tissue ischaemia leads to the accumulation of lactic acid due to

anaerobic glycolysis. As a consequence of the inefficient energy

production due to anaerobic metabolism, the ATP stores deplete

and the energy-dependent cellular membrane ion pumps fail.

These intracellular events lead to increased membrane perme-

ability and cellular and tissue oedema.1

The second stage of this pathophysiological cascade is char-

acterised by terminal membrane depolarisation along with

excessive release of excitatory neurotransmitters (glutamate and

aspartate), activation of N-methyl-D-aspartate, a-amino-3-

hydroxy-5-methyl-4-isoxazolpropionate, and voltage-dependent

Katharine Hunt MBBS FRCA is a Consultant Anaesthetist at the National

Hospital for Neurology and Neurosurgery, London, UK. Conflicts of

interest: none declared.

Surbhi Virmani FRCA is a Specialist Registrar in Anaesthesia at the

National Hospital for Neurology and Neurosurgery, London, UK.

Conflicts of interest: none declared.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 15:4 168

calcium (Ca2þ) and sodium (Naþ) channels. The consequent

Ca2þ and Naþ influx, in turn, lead to catabolic intracellular

processes. Ca2þ activates lipid peroxidases, proteases, and

phospholipases that increase the intracellular concentration of

free fatty acids and free radicals. These, along with activation of

endonucleases, translocases and caspases lead to structural

disintegration of cellular membranes and nucleosomal DNA

causing DNA fragmentation and inhibition of DNA repair.

Thefinal stageof the cascade is an increase inexpressionof genes

determining programmed cell death leading to necrosis (apoptosis).

Different parts of the brain respond differently to the same

insult with some areas being more vulnerable compared to others.

Cerebral neuroprotection

There are physiological, pharmaceutical and surgical measures

that can be put in place to provide cerebral neuroprotection.

Ideally these should be instituted before the onset of the

ischaemic process as close to the onset of the primary brain insult

as possible. Cerebral protection involves creating the most

C Cytotoxic

C Interstitial

C Infection

� Meningitis

� Brain abscess

C Infarction

Box 1

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NEUROSURGICAL ANAESTHESIA

favourable conditions possible for the brain to ensure optimal

functioning as a long-term objective (Box 2).

Physiological strategies for neuroprotection

Control of hypoxaemia: hypoxaemia, defined as arterial oxygen

tension (PaO2) <8 kPa, is associated with a significant increase in

mortality in patients with severe traumatic brain injury (TBI),

defined as those patients with a Glasgow Coma Score (GCS) <8.

A low brain tissue oxygen tension often indicates ongoing cere-

bral ischaemia. Aggressive correction of hypoxaemia is manda-

tory and may require early tracheal intubation and mechanical

ventilation in the most severe of cases. Current guidelines sug-

gest that a PaO2 >13 kPa should be targeted.2

Blood pressure control: after an insult to the brain, autoregulation

is diminished or lost;with the consequence that cerebral bloodflow

(CBF) becomes directly related to systemic mean arterial pressure.

Even moderate hypotension (systolic blood pressure [SBP] <90

mmHg) is associated with a twofold increase in mortality in pa-

tients with TBI. Current guidelines recommend that while no spe-

cific number should be targeted, even a single episode of SBP <90

mmHg should be avoided. Hypotension should be managed with

aggressive fluid resuscitation and, if necessary, vasoactive agents.2

Temperature control andhypothermia: in experimentalmodels of

brain injury, hypothermia has been shown to decrease the cerebral

metabolic rate to a degree of 7% per degree Celsius fall in temper-

ature. It not only slows metabolic processes but also immune and

inflammatory responses to injury. Hypothermia also obtunds

neurotransmitter release and therefore prevents apoptosis.

This process, however, has not been demonstrated clinically,

and despite these findings, for most conditions there is no

improvement in morbidity or mortality due to induced hypo-

thermia. Induced hypothermia may also cause sepsis, coagulo-

pathies and arrhythmias, particularly in patients with existing

risk factors for these conditions. It is therefore not routinely

recommended in the majority of cases.3

Cerebral protection strategies

Physiological

C Blood pressure control

C Maintenance of oxygenation

C Arterial carbon dioxide control

C Temperature control

C Glycaemic control

Pharmacological

C Propofol

C Thiopental

C Benzodiazepines

C Volatile anaesthetic agents

C Hyperosmolar agents

C Nimodipine

C Magnesium

Surgical

C Decompressive craniectomy

Box 2

ANAESTHESIA AND INTENSIVE CARE MEDICINE 15:4 169

There is a role for hypothermia, however, in comatose pa-

tients following ‘return of spontaneous circulation’ post cardiac

arrest, and current guidelines recommend an induction of a mild

hypothermia (32e34 �C) for 12e24 hours post cardiac arrest

followed by a controlled rewarming.

Glycaemic control: there is a direct and proven relationship be-

tween hyperglycaemia and poor outcome after brain injury. By the

same adage, hypoglycaemia is also detrimental to neurological

recovery, so insulin-induced hypoglycaemia must be avoided. For

the purposes of neuroprotection, reasonable control of blood

glucose levels (�10mmol/litre) should bemaintained at all times.

Seizures: seizures compromise the oxygen and substrate supply to

the brain. They may be difficult to detect in comatose patients and

the only sign could be failure to recover from neuromuscular

blockade after surgery or prolonged sedation and ventilation. As

seizures can be inconspicuous, yet vital in depleting the brain

tissue of resources, early recognition through clinical examination

and investigation such as an electroencephalogram (EEG), along

with early treatment is important (see Pharmacological strategies).

Hypercapnia and hypocapnia: it is recognised that in hypercap-

nic patients, a 1 kPa change in arterial carbon dioxide (PaCO2)

increases CBF by 25e35%.1 Conversely, in hypocapnia a 1 kPa

change in PaCO2 decreases CBF by 15%. There aremaximal effects

to the changes in CBF above 10e11 kPa and below 2.5 kPa.4,5

Hyperventilation to achieve hypocapnia in patients used to be

popular when treating brain injury. However, while the response

to changes in PaCO2 is prompt, with a half life of 20 seconds, this

response is not sustained long term, wearing off after between 6

and 12 hours of hypocapnia. There is also evidence that exces-

sive hyperventilation may worsen perfusion to some ischaemic

areas of the brain following a TBI. Current guidelines suggest that

PaCO2 is maintained between 4.5 and 5 kPa and although hy-

perventilation may be considered in cases of severe brain injury,

blood flow and oxygen delivery to the brain must be monitored

closely during this intervention.

Pharmacological strategies for neuroprotection

Thiopental reduces the cerebral metabolic rate and cerebral

blood flow and is also an anti-epileptic drug.

Historically, this drug has been frequently used to manage

TBI; however, dosing needs to be closely monitored due to the

hypotensive effects of this agent, and indeed, there is no clear

evidence that it confers improved neurological outcome. Due to

its principal side effect of hypotension and its tissue accumula-

tion (terminal half life of 11 hours), it is now not favoured as a

first-line sedative agent, and is only considered as a second-line

agent when all other strategies have failed.

Propofol offers neuroprotection as both cerebral metabolic rate

and CBF are reduced in a dose-dependent manner with use of

this agent, such that an isoelectric EEG may be achieved.

Epileptiform movements have been observed with its use but

there is no evidence to suggest that these are due to cortical

seizure activity or epilepsy. Propofol has a shorter half life than

thiopental (terminal half life of 3e4 hours) and is therefore a

favoured sedative agent. Prolonged infusions are associated with

� 2014 Elsevier Ltd. All rights reserved.

NEUROSURGICAL ANAESTHESIA

propofol infusion syndrome so patients treated with long-term

infusions of this agent (more than 48 hours and at doses greater

than 5 mg/kg/h) should be monitored closely.

Benzodiazepines offer neuroprotection, but to a much lesser

extent than propofol or thiopental. They also act by reducing CBF

and cerebral metabolic rate. They have a place in co-induction,

long-term sedation, and as anticonvulsants in the treatment of

some cerebral diseases.

Volatile agents: all volatile agents lead to cerebral vasodilatation

and also suppress cerebral metabolism. A balance between these

two determines the final response. At lower concentrations they are

similar to the intravenous agents and they offer neuroprotection by

suppressing neuronal energy requirements, however, at higher

levels, they increase the CBF due to vasodilatation. Sevoflurane has

the least effect on CBF of all the currently available agents.

Hyperosmolar therapy: there are currently two osmotic agents

commonly used for their effects on cerebral oedema and raised

intracranial pressure (ICP).

Mannitole decreases ICP by reducing blood viscosity, which in

turn results in increased blood flow leading to vasoconstriction

secondary to an increased oxygen delivery. In addition, it has also

been shown to decrease the rate of cerebral spinal fluid (CSF)

formation.

In the presence of an intact bloodebrain barrier, mannitol

draws out water from brain tissue into the plasma via osmosis;

however, the agent should be used with caution, as in a non-

intact bloodebrain barrier the molecules may leak into the

tissue themselves and cause tissue oedema through the same

osmotic effect in the opposing direction.

Hypertonic saline e may be as effective asmannitol in reducing

ICP. In studies comparing this agent to mannitol, it is not as effi-

cacious in some conditions such as sub-arachnoid haemorrhage

but has a role in TBI with a disrupted bloodebrain barrier.6,7

Apart from acting as an osmotic agent like mannitol, it also

causes endothelial cell dehydration thereby increasing the lumen

of blood vessels and increasing cerebral perfusion.

It is also known to restore neuronal membrane potential and

has an anti inflammatory effect on the neural cells.

Sodium bicarbonate: use of sodium bicarbonate to lower intra-

cranial pressure is still under investigation but has shown

promising results in the initial but small isolated studies. These

studies have used 85 ml of 8.4% sodium bicarbonate instead of

100 ml hypertonic saline and have noted that a single dose of

8.4% sodium bicarbonate is as effective at treating rises in ICP

for at least 6 hours without exposing patients to the risks of a

hyperchloraemic metabolic acidosis.8

Nimodipine is a cerebro-selective calcium channel blocker used

in the treatment of subarachnoid haemorrhage. It improves

outcome by preventing vasospasm associated with subarachnoid

haemorrahge and also by exerting neuroprotective effects. There

is no evidence for a beneficial role of this drug in TBI.

Corticosteroids reduce cerebral oedema around brain tumours

and are therefore commonly used for this condition; however,

ANAESTHESIA AND INTENSIVE CARE MEDICINE 15:4 170

there is no evidence of them lowering ICP or improving outcome

after TBI or stroke.

They are immunosuppressive and may cause hyperglycaemia

unless closely monitored.

Magnesium is a calcium antagonist that can also antagonise

NMDA receptors and glutamate release and has been shown to

improve outcome after subarachnoid haemorrhage but can

worsen outcome in TBI. Its only current routine use is in hypo-

magnesaemic patients.9

Surgical strategies for cerebroprotection-decompressive

craniectomy

The aim of a decompressive craniectomy is to relieve the tension

on the brain tissue enclosed in the cranial vault by removing part

of the skull bone, thus giving brain tissue space to expand and

therefore decreasing the ICP and improving cerebral perfusion.

While it is known to convert mortality following a middle

cerebral artery brain infarct from 60% to 20% and to decrease

mortality in TBI patients, the opinions on the benefits of this

procedure are divided.

There is no doubt that the procedure improves survival in

many patients who would otherwise die of a raised ICP that has

failed to respond to other measures. However, it has been noted

that many of these patients actually survive to have a poor

quality of life after surgery (persistent vegetative state) and

therefore one should question whether the results justify this

treatment in all patients.10 A

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� 2014 Elsevier Ltd. All rights reserved.